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Accession Type:
Pathway
CO_activation_
of_GC
sGC
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Molecule List for pathway sGC (Pathway Number 140)

 Name Initial Conc. (uM) Volume (fL) Buffered
15prime_GMP00.0016667No
   
2cGMP00.0016667No
   
3CO00.0016667No
    CO is an endogenous modulator of sGC. It is produced by the oxidative cleavage by HO to yield CO and Biliverdin. It also binds to the heme group on sGC as NO and it may be competetive to NO with regard to the binding to the heme prosthetic group. Like NO, it binds to the Iron in the heme, and activate Guanylyl Cyclase. (Brune et al., 1987, Mol. Pharmacol.32, 497-504), Kharitonov et al., 1995, PNAS, 92:2568-2571) Because of the gaseous nature of CO, and its high affinity for hemoprotein, its very difficult to determine the exact intracellular concentration of CO. Endogenous CO level was calculated to be 50-160 pmol/mg protein or 10-30 uM, by Ingi et al., J Neursoci 1996, 16(18): 5621-5628, on the assumption that the amount of CO produced for 10-30 mins is an effective concentration in the cell, taking into account the diffusion of CO. Using exogenous CO at the endogenous levels of 10-30 uM, significant elevation of GC activity is observed, though CO does not seem to be a rapid stimulator, but works as a modulator, producing slower and long-term effects (Ingi et al., 1996, J Neurosci.,16(18):5621-5628).
4COHb00.0016667No
    Carboxy Hemoglobin, from which CO subsequently is released into the alveolar space of the lung, where molecular oxygen is alternately bound to the heme. Most of the CO generated in the body is thus exhaled into the airway. (Suematsu M, personal correspondence)
5dissoCO0.11420.0016667Yes
    The erythrocyte-associated hemoglobin has a critical role of being the primary CO-scavenging system. Locally generated CO is eliminated by hemoglobin in circulating erythrocytes and is gradually released into the alveolar space of the lung, where molecular oxygen is alternately bound to the heme. Most of the CO (Carbon Monoxide) generated in the body is exhaled into the airway. (Suematsu M, Gasteroenterology 2001;120:1227-1240 and personal correspondence)
6Ery_HbO250.0016667No
    Erythrocyte associated hemoglobin -- This supposedly is the primary CO-scavenging system. (Suematsu M, personal correspondence)
7GC5_CO00.0016667No
    The active five coordinate Carboxy GC. Kharitonov et al., PNAS, 1995, 92:2568-2571 report the presence of a five coord carboxy species during the activation of GC by CO, similar to the presence of a five coord species in the nitroxyl GC, during NO activation of sGC.
8GC6-CO00.0016667No
    The six-coordinate form of sGC bound to CO. This mechanism has been proved with results by Kharitonov et al., PNAS, 1995, 92:2568-2571. Most of the Carboxy derivative of GC is six-coordinate.
9GTP10000.0016667Yes
    Under in vivo conditions, GTP is present in excess, ~ 1mM.
10Heme11.30.0016667No
    Total cellular heme determined spectrophotometrically to be 1.5 nmol/mg protein. (Ingi et al., 1996, Neuron,16:835-842), a value resembling reported heme content in neuronal tissues. Ingi et al., also reports in J Neurosci. 1996,16(18):5621-5628, that Brain has significant levels of heme (1.3 nmol/mg protein) Conc calculated/used 21.3
11Hemeoxyg220.0016667No
    Heme oxygenase 2 (HO-2)-Highly expressed in Brain (Sun et al., 1990, J Biol. Chem., 265: 8212-8217), with discrete neuronal localization demonstrated throughout the brain with in situ hybridisation and immunohistochemical studies (Verma et al., 1993, Science, 259: 381-384). Mol. Wt. of HO-2 is 36 kDa.(Migita et al., JBC,1998,273(2):945-949.) Three mammalian isoforms have been identified. HO-1, is inducible and highly concentrated in tissues and involved in catabolism of heme proteins. HO-3, is an isoform with low catalytic activity, with uncertain physiological role. (Montellano, PRO., 2000, Curr Opin in Chem Biol, 4:221-227)
12PDE50.0016667No
    Phosphodiesterase : Degrades cGMP to 5prime_GMP Conc from Kotera et al., Eur J Biochem., 1997; 249:434-442 and Kuroda et al., J Neurosci, 2001, 21(15):5693-5702
13sGC30.0016667No
    sGC is enriched in purkine cells ~3 uM (Conc from Shinya Kuroda, assumed on the basis of reported data in Ariano et al., 1982, PNAS,79: 297-300) soluble Guanylyl Cyclase localization is virtually identical to that of HO-2 in numerous brain regions.(Ingi et al., 1995, J Neurosci., 15:8214-8222), in contrast to discrepancies in the localization of NOS and sGC in the brain.


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